Raman Spectroscopy for Pharmaceutical Applications

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1 Spectroscopy Solutions 2014 E conference Raman Spectroscopy for Pharmaceutical Applications Frederick H. Long, Ph.D. President, Spectroscopic Solutions, LLC

2 History of Raman Spectroscopy Discovery of Raman effect, CV Raman Near simultaneous discovery by Landsberg & Mandelstam Commercial lasers Charge-coupled detectors Hand held instruments The Raman Effect was discovered in the 1920 s; however, Raman spectroscopy became a practical analytical method with the development of commercial lasers and charge-coupled detectors

3 Molecular Vibrations Vibrations of H 2 O Molecular vibrations are due to the relative motion of the atoms in a molecule. The frequency of the vibrations is characteristic of the chemical bond.

4 IR Absorption IR absorption is associated with a change in the molecular dipole moment. IR spectrum are chemically specific and can be used to identify materials.

5 Near IR Spectroscopy NIR spectra are due to overtones and combination bands of fundamental IR absorptions Overtones are analogous to octaves on a musical scale In practice NIR spectrum are dominated by OH, CH, and NH overtones and combination bands

6 NIR Spectrum of 2 pharmaceutical actives Desloratadine (blue) & Loratadine (red) Absorbance Wavelength (nm) NIR absorption of molecules often show broad peaks. Powered materials often show broad sloping backgrounds.

7 Origin of Raman Scattering: Polarizability Electric field Electron cloud Distorted Electron Cloud Polarizability is the distortion of the electron cloud of a molecule due to an applied electric field. Raman Scattering is due to the change in polarizability as the molecule vibrates.

8 Laser Light Scattering n L n L +n 0 laser n L n L -n 0 Raman scattering typically measures the light scattered at n L -n 0.

9 Raman Scattering Instrumentation detector laser Scattered light (lower frequency) sample The essential parts of a Raman spectrometer are a laser, optics to collect the scattered light and a detector.

10 Raman Scattering Intensity Incident laser light scattered light Excellent Raman samples scatter with an efficiency of about 2x10-8.

11 Typical Raman Spectrum Acetaminophen Raman Spectrum

12 Hand-Held Raman Instrumentation Recently several companies have developed hand-held Raman spectrometers.

13 Raman Calibration Cyclohexane Raman spectrum Calibration of Raman spectrometers is often done using samples of known stable spectra.

14 Raw Material Identification Most common application of Raman Spectroscopy Little or no sample prep required Can examine samples thru some containers

15 Raman Spectrum Specificity An important advantage of Raman Spectroscopy is the clear specificity of the method. Ahura/Thermo Electron

16 Identification Method Equation for wavelength correlation sample set mean x spectra of interest WC x x is a perfect match A mathematical method for identification of spectra is important because subjectivity of comparison is eliminated and it can be automated with computer software. More sensitive comparison methods are available if needed.

17 Finished Product Verification Raman spectroscopy can be used to identify finished products. This figure includes several common over the counter pain medicines.

18 Potential Complications Many finished products are coated. Raman spectroscopy Not be able to measure through the coating. A simple solution to this issue is to remove the coating before measurement Some samples exhibit fluorescence, (emission from excited electronic states) Use 1064 nm laser to minimize fluorescence

19 1064 nm Laser Excitation 1064 nm excitation makes it possible to examine many previously unidentifiable materials. The above example is the OTC drug Excedrin BaySpec

20 785 vs 1064 nm laser excitation street drug Some materials such as street drug require 1064 nm excitation in order to avoid strong background fluorescence

21 Raman/NIR Comparison NIR and Raman are both vibrational spectroscopy methods Many samples can be identified with either NIR or Raman NIR is very sensitive to moisture (H 2 O), Raman is not Raman can be done using a microscope, NIR cannot Raman can be used on many inorganic samples NIR can be used on spatially inhomogeneous samples

22 Raman analysis Raman Spectroscopy of Medical Devices Drug-Eluting Stents (DES) Important therapy for heart patients Powerful drug inhibiting clotting Air Drug Coating Parylene-C Stainless Steel

23 Coating Formulation drug PBMA PEVA Raman Shift (cm-1) The coating on the stent contains the drug and two polymers. The Raman spectra were measured thru a microscope.

24 Residual Residual Variance Regression Coefficient Quantitative Models Using Multivariate Statistics Lab Assay (wt %) Lab Assay (wt %) E E E E E E+00 Quantitative models for the drug, PEVA, and PBMA polymer concentrations were made and validated. These models require multivariate statistics, i.e. chemometrics. 0 Raman shift (cm -1 ) Lab Assay (wt %) Raman shift (cm -1 ) Factors

25 Quantitative Raman Imaging Spectroscopy drug PBMA Quantitative models for the drug, PEVA, and PBMA polymer concentrations were made and validated

26 Acknowledgements The work on Raman imaging of drug eluding stents was done with Cordis Corporation (Johnson & Johnson) Karin Balss, Maureen Chisholm, Vladimir Veselov, Argjenta Orana, Eugena Akerman-Revis, George Papandreou, and Cynthia A. Maryanoff

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